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Acta Clin Croat 2013; 52:523-528 Case Report

Acute disseminated mimicking acute meningoencephalitis

Mahmoud Reza Ashrafi1, Davood Amirkashani1, Armin Hirbod-Mobarakeh2,3,4, Bahareh Yaghmaei1, Alireza Tavassoli1, Farzad Manafi1 and Nima Rezaei1,2,3

1Pediatrics Center of Excellence, Children’s Medical Center; 2Research Center for Immunodeficiencies;3 Molecular Immunology Research Center and Department of Immunology, School of Medicine; 4Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran

SUMMARY – Acute disseminated encephalomyelitis is an inflammatory demyelinating of the central that usually occurs following an antecedent or vaccination. Children and young adults are predominantly affected, but it has low incidence in children younger than 3 years. The disease manifests with a wide range of neurological abnormalities and a variable combination of , , , convulsion and cranial nerve palsies, and there are no pathognomonic clinical or laboratory findings. So, establishment of definitive diagnosis is challen- ging in infants. This challenge may result in delayed diagnosis and consequently delayed treatment of acute disseminated encephalomyelitis, which may cause permanent neurological disability. Here- in, we report an infant with acute disseminated encephalomyelitis, who mimicked the symptoms of meningoencephalitis and the correct diagnosis and treatment were delayed till the development of a severe phase of the disease. Key words: Encephalomyelitis, acute disseminated; Meningoencephalitis; Case report

Introduction among very young patients, especially those below three years of age7. Acute disseminated encephalomyelitis (ADEM) In children, ADEM can present with a prodromal is a monophasic, polysymptomatic disorder resulting phase including fever, malaise, headache, nausea and from inflammatory demyelination of the central ner- 1 vomiting, which usually progresses over hours or days vous system (CNS) white matter . It usually develops to meningeal signs and drowsiness. These symptoms very fast and presents various combinations of motor, represent a diagnostic challenge. In children, espe- sensory, visual and cognitive signs to general pedia- 2-4 cially in infants, the manifestations of ADEM can tricians . The diagnosis is established by evidence of be interpreted by several conditions due to the wide multifocal, hyperintense lesions on fluid-attenuated in- range of possible etiologies. This diagnostic challenge version recovery (FLAIR) and T2-weighted magnetic 3,5 may result in delayed diagnosis until the symptoms of resonance imaging (MRI) scan . ADEM is a rare a severe phase of disease appear. Consequently, delay disease with an estimated incidence of 0.8/100,000/ in treatment may cause permanent neurological dis- year, usually occurring after an infection or vaccina- 4,8 1,6 ability acquired very early in life . tion . The incidence is highest in children but low There are only few cases of infantile ADEM in the literature. The mean age of children with ADEM who Correspondence to: Nima Rezaei, MD, PhD, Children’s Medical Center Hospital, 62 Qarib St., Keshavarz Blvd., Tehran 14194, have been reported in the literature since 1987 was 6.7 Iran years and only rarely there was a case younger than 1 E-mail: [email protected] year8,9. In a study of 28 patients with ADEM, there Received July 17, 2012, accepted January 16, 2013 was not any case of ADEM younger than 3 years10.

523 Acta Clin Croat, Vol. 52, No. 4, 2013 M. R. Ashrafi et al. Acute disseminated encephalomyelitis; bacterial meningoencephalitis

Herein, we report a 3-month-old girl with ADEM, had a birth weight of 3500 g. She had up-to-date im- who mimicked the symptoms of septic meningoen- munization. cephalitis. She was first treated as a case of One week before admission, she had rhinorrhea, and after deterioration of her condition, she was diag- coughing and wheezing. Family physician diagnosed nosed as ADEM. it as a nonspecific upper respiratory tract infection and prescribed amoxicillin and acetaminophen, which Case Report improved the symptoms. Three days prior to admis- sion, she presented fever, fatigue and poor feeding. A 3-month-old girl with a chief complaint of fever Finally, the patient was admitted to the emergency and poor feeding was admitted to emergency depart- department due to exacerbation of these symptoms. ment of the Children’s Medical Center, Pediatrics On admission, she was ill-looking, anicteric and fe- Center of Excellence in Iran. She was the first child brile (tympanic temperature, 38.5 °C), with low state to unrelated parents, was born by cesarean section and of consciousness. She had tachypnea with a respira-

Table 1. Laboratory findings of the patient

Patient Normal range White blood cell count 1750/μL 4.5-11.0 103/μL Red blood cell count 4.1 3.1-4.3 mill/mm3 Reticulocyte count 3% 0%-2.8% Platelet 532000 300-700x103/mm3 Hematocrit 27.1% 29%-42% Neutrophils 62% 17%-45% Lymphocytes 33% 41%-71% Monocytes 4% 4%-7% Eosinophils 0.7% 0%-3% Basophils 0.3% 0%-1% Hemoglobin 9.1g/dL 13.5-17.0 g/dL Mean cellular volume 77.5 fm 74-96 fm C-reactive 15 mg/dL 0-12 mg/dL Erythrocyte sedimentation rate 15 mm/h 0-20 mm/h Lymphocyte markers: CD3 76% 49%-76% CD4 60% 31%-63% CD19 11.9% 14%-37% CD8 16.6% 17.4%-34.2% Arterial blood gas: pH 7.44 7.35-7.45

PCO2 25 mm Hg 35-45 mm Hg

HCO3 17 mEq/L 19-25 mEq/L : White blood cell count 42/µL (80%Lymph) 0.7 WBC/mm3 Red blood cell count 2 0 Glucose 57 mg/dL 40-80 mg/dL Protein 25 mg/dL 5-40 mg/dL

524 Acta Clin Croat, Vol. 52, No. 4, 2013 M. R. Ashrafi et al. Acute disseminated encephalomyelitis; bacterial meningoencephalitis tory rate of 48/min. The patient had neither diarrhea On day 3, the patient developed focal nor vomiting. She had had low urine volume from the with upward gaze on the right eye and bilateral tonic previous day. The patient had nothing abnormal on movements in the limbs with right-sided dominance. physical examination and also neck stiffness was ab- These seizures repeated 3 times within 2 hours; so, sent, but she had a slight bilateral palpebral . phenobarbital was administered to the patient. After Urine and blood culture, serology for human immu- 8 hours, phenytoin was added to drug regimen due to nodeficiency (HIV), cytomegalovirus (CMV), another event of , which improved the patient’s Epstein-Barr virus (EBV), HHV6, influenza, herpes condition. Electroencephalography (EEG) was not simplex (HSV) and typhoid and paratyphoid remarkable for . Computed tomography (CT) A and B fever were done and were all negative. Labo- scan of the was performed, which revealed mild ratory results for blood revealed normocytic anemia prominence of the frontal lobe gyri, widening of the with mild respiratory alkalosis and increased inflam- sylvian fissure, minimal prominence of the lateral matory markers (Table 1). Immunologic tests were ventricle, and excess of extra-axial fluid. Dexametha- all within the normal range. Lumbar puncture was sone (0.15 mg/kg every 6 hours) was added to drug performed and cerebrospinal fluid (CSF) analysis re- regimen to prevent focal neurological deficits of prob- vealed with lymphocytic predominance. able meningitis. On day 4, the patient’s general status Due to the presence of fever and inflammatory including fever, consciousness and respiratory distress changes in blood and CSF, the initial diagnosis was improved dramatically. Dexamethasone was stopped, infective meningoencephalitis, especially herpes sim- but several hours later, the patient presented right eye plex meningoencephalitis; therefore, empirical treat- deviation and anisocoria (right pupil mitotic and left ment with ceftriaxone, vancomycin and acyclovir was mydriatic). A positive Babinski sign in the right foot started. In the next few hours, the patient showed was seen too. In the next hours, the patient developed signs of respiratory distress. In the meantime, CSF fatigue and low grade fever. On MRI, disseminated was analyzed for HSV, HHV7, influenza, H1N1 us- demyelinated lesions in the right periventricular re- ing the polymerase chain reaction (PCR), with nega- gion, left cerebellum and brain stem were seen. Con- tive results. sidering the signs, MRI results and exclusion of other

Fig. 1. Magnetic resonance images of the brain before treatment, fluid-attenuated inversion recovery (FLAIR) sequence.

Acta Clin Croat, Vol. 52, No. 4, 2013 525 M. R. Ashrafi et al. Acute disseminated encephalomyelitis; bacterial meningoencephalitis possible etiologies, the diagnosis of ADEM was es- ease may remain unsuspected and without appropri- tablished (Fig. 1). Therefore, corticosteroid therapy ate treatment would develop to severe phase and pres- was started with prednisolone (2 mg/kg/day), while ent with cranial nerve palsies and generalized or focal were stopped. On day 3 of corticosteroid seizures11,12. As there are no pathognomonic clinical therapy, all the symptoms including fever improved. or laboratory findings for ADEM, even on brain CT Taking brain stem lesions into consideration, the or MRI, the physician can take ADEM in consider- auditory brainstem response (ABR) test was taken, ation only through a careful process of exclusion of which yielded normal result. Corticosteroid therapy other diseases4,19. These laboratory tests often delay was continued with a tapering dose of oral prednisone the establishment of ADEM diagnosis and appropri- for 6 weeks. ate treatment. The first and most important differential diagnosis Discussion in the early phase of ADEM, especially in infants, is acute viral, bacterial, or parasitic meningoencepha- Acute disseminated encephalomyelitis is a rare de- 2,4,8,15,20 myelinating disorder of the white matter of the CNS litis, especially HSV meningoencephalitis . 1,5,6 Meningoencephalitis has the same initial clinical fea- with highest incidence in childhood . Although it 8 has a wide range of clinical manifestations, includ- tures as ADEM (fever, , and confusion) . ing various combinations of motor, sensory, visual and ADEM usually begins after a nonspecific upper re- cognitive symptoms, it usually begins with systemic spiratory tract infection, so the physician may assume symptoms like fever, malaise, myalgia, headache, the antecedent infection if ADEM has extended to 11,12 the and brain and misinterpret the symp- nausea, and vomiting . The severe course of the 21 disease can be presented by a variable combination of toms as meningoencephalitis . If this event is too convulsions, cranial nerve palsies, visual field deficits, close to presentation of ADEM, this would be even more disguising, as in our patient. The latency period language disturbances, mental status abnormalities, 2,4 and psychiatric changes in children3,11,12. Seizures are takes 4 to 21 days on average . The reason for the mainly seen in severe cases in children younger than short latency period in our patient may have been the 5 years2,13. Our patient in the early phase of disease immaturity of the CNS myelin or age related differ- presented with just a low grade fever, fatigue and poor ences in the patient’s immune response in comparison feeding, and due to the delay in diagnosis and con- to adults. sequently mistreatment rapidly developed seizures as Laboratory findings in ADEM, which are the a manifestation of a severe phase of the disease. In same as in septic meningoencephalitis, show an in- our patient, the course of development of symptoms flammatory profile such as elevated white cell count, and their improvement in response to corticosteroids erythrocyte sedimentation rate and C-reactive pro- 17 were more rapid than usual. These findings suggest tein . Even by CSF, the physician cannot exclude sep- an aggressive form of the disease, which may be age- tic meningitis, as the CSF profile in ADEM shows related14. lymphocytic pleocytosis or polymorphonuclear leu- 7 Timely diagnosis of ADEM is of great importance kocytosis in early phases . In addition, atypical CSF because delay in treatment may result in permanent profile in infantile ADEM may delay the diagnosis. neurologic disorder2,15. In infants, in-time diagnosis For instance, the total protein content in CSF is usu- 7 can be compromised by a number of factors. The rar- ally increased , but in the presented case there was no ity of infantile ADEM is one of the most important increase in the CSF protein content. CT scan most factors that may delay suspicion and thus the diagno- of the time is unrevealing but may show evidence of sis of ADEM. In infants, the systemic symptoms of CSF excess mostly due to inflammatory reactions17. the early phase of the disease present as some more The evidence of CSF excess in our patient’s CT scan nonspecific symptoms, such as poor feeding, fatigue was a misleading factor, which was interpreted as a and fever. These symptoms in infants represent a di- consequence of meningoencephalitis. After the epi- agnostic challenge as they can be caused by a wide sodes of seizure, EEG may be done, which usually range of possible etiologies8,16-18. Therefore, the dis- does not demonstrate any significant changes7.

526 Acta Clin Croat, Vol. 52, No. 4, 2013 M. R. Ashrafi et al. Acute disseminated encephalomyelitis; bacterial meningoencephalitis

The most valuable test for the diagnosis of ADEM 3. muRTHY SN, FADEN HS, COHEN ME, BAKSHI R. is MRI, although no imaging criteria have been Acute disseminated encephalomyelitis in children. Pediatrics 2002;110:e21. identified for ADEM7,22. Inflammatory demyelinat- 4. menge T, HEMMER B, NESSLER S, WIENDL H, ing white matter lesions, as hallmarks of ADEM, NEUHAUS O, HARTUNG HP et al. Acute disseminated are most frequently identified on T2-weighted and encephalomyelitis: an update. Arch Neurol 2005;62:1673-80. FLAIR sequences. These asymmetric lesions usu- 5. muRTHY JM. Acute disseminated encephalomyelitis. Neu- ally involve the subcortical and central white matter rol India 2002;50:238-43. in children and in 30%-60% of cases they may also 6. menge T, KIESEIER BC, NESSLER S, HEMMER B, involve periventricular white matter8. The MRI of HARTUNG HP, STUVE O. Acute disseminated encepha- the patient presented also revealed lesions in the cer- lomyelitis: an acute hit against the brain. Curr Opin Neurol ebellum and brainstem, which are common sites of 2007;20:247-54. involvement in children2. 7. WENDER M. Acute disseminated encephalomyelitis (ADEM). J Neuroimmunol 2011;231:92-9. Treatment of infantile ADEM is an enigma. The 8. tenemBAUM SN. Disseminated encephalomyelitis in fatality rate of ADEM is 10%-25%, with neurologic children. Clin Neurol Neurosurg 2008;110:928-38. deficits in up to 40% of survivors7,9. Due to the low 9. dAVIS LE, BOOSS J. Acute disseminated encephalomy- incidence of ADEM, currently there is no controlled elitis in children: a changing picture. Pediatr Infect Dis J trial concerning treatment of ADEM, so therapies for 2003;22:829-31. 7 ADEM are just based on clinical data . We used cor- 10. dALE RC, De SOUSA C, CHONG WK, COX TC, ticosteroid therapy as the first-line treatment to im- HARDING B, NEVILLE BG. Acute disseminated enceph- prove and inflammatory process in the alomyelitis, multiphasic disseminated encephalomyelitis and brain7,17,23. Although the efficacy of corticosteroids has in children. Brain 2000;123 Pt 12:2407-22. not been well established, the result of this treatment 11. young NP, WEINSHENKER BG, LUCCHINETTI CF. Acute disseminated encephalomyelitis: current under- in our patient was favorable, since dramatic improve- standing and controversies. Semin Neurol 2008;28:84-94. ment was seen even with a low dose of dexamethasone. 12. HYNSON JL, KORNBERG AJ, COLEMAN LT, SHIELD Herpetic meningoencephalitis should be excluded as a L, HARVEY AS, KEAN MJ. Clinical and neuroradiologic probable differential diagnosis before treatment with features of acute disseminated encephalomyelitis in children. corticosteroids, as it is a contraindication. It is recom- 2001;56:1308-12. mended to use appropriate and acyclovir to 13. tenemBAUM S, CHAMOLES N, FEJERMAN N. eliminate possible meningoencephalitis until the di- Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology 2002;59:1224-31. agnosis of ADEM is definitely established17. In conclusion, infantile ADEM is difficult to diag- 14. CARSTAIRS SD, CARSTAIRS KL. Emergency depart- ment presentation of acute disseminated encephalomyelitis. nose and manage at the clinical level. It is important Pediatr Emerg Care 2007;23:109-11. to establish a correct diagnosis at an early stage, since 15. FUJIKI F, TSUBOI Y, HORI T, YAMADA T. Aseptic permanent neurological damages may be prevented by meningitis as initial presentation of acute disseminated en- rapid corticosteroid therapy2,15. General pediatricians cephalomyelitis. J Neurol Sci 2008;272:129-31. should consider the diagnosis of ADEM in children 16. mihiĆ J, ROTIM K, MARCIKIĆ M, SMILJANIĆ D. with meningism, fever and acute , es- Head injury in children. Acta Clin Croat 2011;50:539-48. pecially when they appear after an infection or vac- 17. stonehouse M, GUPTE G, WASSMER E, WHITE- cination4. In this condition, most of the time an early HOUSE WP. Acute disseminated encephalomyelitis: recog- 22,24,25 nition in the hands of general paediatricians. Arch Dis Child MRI will help the physician suspect ADEM . 2003;88:122-4. 18. CRNKOVIĆ M, MATIJEVIĆ-MIKELIĆ V, DEMARIN References V, KOŠIČEK T, MOROVIĆ S, GRAZIO S. Risk factors for gross motor dysfunction of lower limbs in children. Acta Clin 1. tenemBAUM S, CHITNIS T, NESS J, HAHN JS. Acute Croat 2011;50:361-6. disseminated encephalomyelitis. Neurology 2007;68:S23-36. 19. mARCHIONI E, TAVAZZI E, MINOLI L, Del BUE S, 2. gARG RK. Acute disseminated encephalomyelitis. Postgrad FERRANTE P, PICCOLO G et al. Acute disseminated en- Med J 2003;79:11-7. cephalomyelitis. Neurol Sci 2008;29 Suppl 2:S286-8.

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20. HARLOFF A, RAUER S, HOFER M, KLISCH J, ELS T. fect of stress hormones on cerebral hemodynamics in patients Fulminant acute disseminated encephalomyelitis mimicking with chronic posttraumatic stress disorder. Acta Clin Croat acute bacterial menigoencephalitis. Eur J Neurol 2005;12:67-9. 2009;48:405-11. 21. CHOWDHARY J, ASHRAF SM, KHAJURIA K. 24. IVANKOVIĆ M, DEMARIN V. From recurrent peripheral with acute disseminated encephalomyelitis (ADEM). Indian facial palsy to multiple sclerosis. Acta Clin Croat 2011;50:419- Pediatr 2009;46:72-4. 21. 22. OKUN MS, MILLAR B, WATSON R. Early diagnostic 25. BAŠIĆ KES V, CESARIK M, ĆORIĆ L, ZAVOREO I, magnetic resonance imaging in acute disseminated encepha- ROTIM K, BEROŠ V et al. Tumor-like multiple sclerosis. lomyelitis. South Med J 2000;93:793-6. Acta Clin Croat 2012;51:113-6. 23. dikANOVIĆ M, KADOJIĆ D, DEMARIN V, TRKA- NJEC Z, MIHALJEVIĆ I, BITUNJAC M et al. The ef-

Sažetak

AKUTNI DISEMINIRANI ENCEFALOMIJELITIS KOJI IZGLEDA KAO AKUTNI MENINGOENCEFALITIS

M. Reza Ashrafi, D. Amirkashani, A. Hirbod-Mobarakeh, B. Yaghmaei, A. Tavassoli, F. Manafi i N. Rezaei

Akutni diseminirani encefalomijelitis je upalna demijelinizirajuća bolest središnjega živčanog sustava koja se najčešće javlja nakon prethodne infekcije ili cijepljenja. Uglavnom zahvaća djecu i mlađe odrasle osobe, ali ima nisku incidenciju u djece mlađe od tri godine. Bolest se očituje širokom lepezom neuroloških nenormalnosti i različitim kombinacijama groznice, glavobolje, meningizma, konvulzija i paralize kranijskih živaca, a nema nikakvih karakterističnih kliničkih ili laboratorijskih nalaza. Stoga je kod dojenčadi postavljanje konačne dijagnoze vrlo zahtjevno, što može dovesti do kašnjenja u dijagnozi i posljedično zakašnjelog liječenja, a to opet može uzrokovati trajne neurološke posljedice. Ovdje prikazujemo slučaj dojenčeta s akutnim diseminiranim encefalomijelitisom, kod kojega su simptomi bili slični simptomima meningo- encefalitisa pa je zakašnjelo postavljanje točne dijagnoze, a time i liječenje dovelo do razvoja teže faze bolesti. Ključne riječi: Encefalomijelitis, akutni diseminirani; Meningoencefalitis; Prikaz slučaja

528 Acta Clin Croat, Vol. 52, No. 4, 2013